Richard K. Watt
B.S. Biochemistry, Brigham Young University (1993)
Ph.D. Biochemistry, University of Wisconsin-Madison (1998)
Postdoctoral Research, Princeton University (1998-2000)
Biological systems require trace amounts of transition metal ions to sustain life. Transition metal ions are required at the active sites of many enzymes for catalytic activity. In fact, transition metals catalyze some of the most energetically demanding reactions in biology. Unfortunately, these highly reactive metal ions also catalyze reactions that are dangerous for biological systems, especially if the metal ion is free in solution. For this purpose biology has evolved elaborate transition metal ion handling systems to bind and sequester transition metal ions in non-reactive environments to prevent these dangerous reactions from occurring. The Watt lab focuses on how iron is properly moved throughout the body.
A healthy individual possesses iron trafficking systems to absorb iron from the diet, transport iron in the bloodstream and deliver iron to cells that require iron. The failure or inhibition of these iron trafficking systems results in free iron that is a potent catalyst to form reactive oxygen species or oxidative stress.
The Watt lab studies diseases where iron trafficking is disrupted and oxidative stress is elevated. Such conditions include Alzheimer’s disease, Parkinson’s disease, kidney disease, Diabetes along with other conditions.
Anemia of Chronic Inflammation Caused by Hepcidin.
Hepcidin is an iron regulatory hormone induced by inflammation that degrades the iron transport protein ferroportin. Hepcidin causes a condition known as anemia of chronic inflammation. Ferroportin is required to transport iron into the bloodstream from the intestinal cells that absorb iron from the diet. Ferroportin also exports iron from the liver, and spleen into the bloodstream where transferrin binds iron and delivers iron to the bone marrow for red blood cell synthesis. The Watt lab has identified hepcidin inhibitors that prevent hepcidin production and stabilize ferroportin. Studies in rats show that iron delivery to the bone marrow is restored using these hepcidin inhibitors.
Caption – Inflammation produces hepcidin that binds to and degrades ferroportin. This stops iron delivery to the bone marrow. Inflammation also blocks EPO production and secretion from the kidneys. Combined these effects decrease red blood cell synthesis.
Caption– FerroMobilin Drug effect. FerroMobilin drugs block hepcidin production so ferroportin is not degraded. Iron is released from the liver and loads transferrin for iron delivery to the bone marrow. Depending on the cytokines that triggered the inflammatory process EPO may be present or ESA drugs may be required to stimulate red blood cell synthesis.
Inhibitors of Iron Binding Proteins
The Watt lab has focused on metabolites that build up in diseases with oxidative stress. We identified metabolites that disrupt iron loading into ferritin and transferrin. In Chronic kidney disease, serum phosphate levels increase because the kidneys are not properly filtering phosphate from the bloodstream. We demonstrated that elevated phosphate inhibits iron loading into ferritin and transferrin by forming insoluble iron phosphate complexes. We are now focusing on other elevated metabolites to determine if they also disrupt normal iron loading or release of iron from ferritin or transferrin.
Caption: As Fe3+ is exported from the cell into the bloodstream it encounters a variety of serum molecules that can react with Fe3+ and form complexes that are not substrates for loading into apo transferrin. This work shows that citrate and albumin can prevent these dangerous side reactions and mediate iron delivery to apo transferrin to prevent the formation of non-transferrin bound iron.
Iron dysregulation is intimately connected to Alzheimer’s disease (AD) but the direct connections are not clear. A new hypothesis relating to homocysteine disrupting iron loading into ferritin might explain the elevated cytosolic iron and oxidative stress. The inability to load iron into ferritin results in elevated cytosolic iron which upregulates expression of the Amyloid Precursor Protein (APP). Homocysteine also inhibits the phosphatase that dephosphorylates tau leading to elevated hyper-phosphorylated tau and tau tangles. In collaboration with Dr. Jonathan Wisco in the BYU PDBio department, we are testing this hypothesis.
For each of the situations outlined above, we are developing point of care diagnostic methods to evaluate known biomarkers. The goals of the diagnostics research are two-fold. First, we are modifying and developing new methods related to antibody detection methods to provide increased sensitivity for this type of analysis. We also focus on particular biomarkers that give diagnostic information to aid clinical practitioners identify the most beneficial and effective treatment.
Matias, C., Belnap, D. W., Smith, M. T., Stewart, M. G., Torres, I. F., Gross, A. J., Watt, R. K., Citrate and albumin facilitate transferrin iron loading in the presence of phosphate, J. Inorg. Biochem., 168 (2017) 107–113.
Swensen, A. C., Finnell, J. G., Matias, C, Gross, A. J., Prince, J. T., Watt, R. K., Price, J. C., Whole blood and urine bioactive Hepcidin-25 determination using liquid chromatography mass spectrometry. Analytical Biochemistry (2017), 517, 23-30.
Watt, R. K., A Unified Model for Ferritin Iron Loading by the Catalytic Center: Implications for Controlling “Free Iron” during Oxidative Stress. ChemBioChem (2013), 14, 415-419.
Hilton, R. J., Andros, N. D., Watt, R. K., The Ferroxidase Center is Essential for Ferritin Iron Loading in the Presence of Phosphate and Minimizes Side Reactions that Form Fe(III)-Phosphate Colloids. BioMetals (2012) 25 (2), 259-273.
Hilton, R. J., Seare, M. C., Andros, N. D., Kenealley, Z., Watt, R. K., Phosphate Inhibits In Vitro Fe3+ Loading into Transferrin by Forming a Soluble Fe(III)-Phosphate Complex: A Potential Non-Transferrin Bound Iron Species. J. Inorg. Biochem. (2012) 110, 1-7.
Watt, R.K., The many faces of the octahedral protein ferritin (Invited Review), BioMetals, (2011) 24 (3), 489-500.
Orihuela, R., Fernández, B., Atrian, S., Watt, R. K., Domínguez-Vera, J. M., Capdevila, M. Ferritin and Metallothionein: Dangerous Liaisons. Chem. Comm. (2011) 28, 47(44). 12155-7.
Shin, K.M., Watt, R.K., Watt, G.D., Choi, S.H., Kim, H.H., Kim, S.I., Kim, S. J., Electrochimica Acta, 2010, 55, 3486-3490. Characterization of ferritin core on redox reactions as a nanocomposite for electron transfer.
Hilton, R.J., Keyes, J.D., Watt, R.K., SPIE, 2010, 7646, 764607, 1-10. Photoreduction of Au(III) to form Au(0) nanoparticles using ferritin as a photocatalyst.
Hilton, R.J., Keyes, J.D., Watt, R.K., SPIE, 2010, 7646, 76460J, 1-8. Maximizing the efficiency of ferritin as a photocatalyst for applications in an artificial photosynthesis system
Zhang, B., Watt, R. K., Galvez, N., Dominguez-Vera, J. M., Watt, G. D., Rate of Iron Transfer through the Horse Spleen Ferritin Shell Determined by Formation of Prussian Blue and Fe-Desferrioxamine in the Ferritin Cavity. Biophysical Chemistry (2006) 120, (2) 96-105.
Tyryshkin, A. M., Watt, R. K., Baranov, S. V., Dasgupta, J., Hendrich, M. P., Dismukes, G. C., Spectroscopic evidence for Ca2+ involvement in the assembly of the Mn4Ca cluster in the photosynthetic water-oxidizing complex. Biochemistry (2006) 45, (43) 12876-12889.